In spite of numerous advances in medical research, cancer remains a leading cause of death in the United States. Traditional modes of clinical care, such as surgical resection, radiotherapy and chemotherapy, have a significant failure rate, especially for solid tumors. Failure occurs either because the initial tumor is unresponsive, or because of recurrence due to re-growth at the original site and/or metastases. The etiology, diagnosis and ablation of cancer remain a central focus for medical research and development.
Since the probability of complete remission of cancer is, in most cases, greatly enhanced by early diagnosis, it is desirable for physicians to be able to identify cancerous tumors as early as possible. Identification of cancerous cells based on changes in gene expression is desirable because changes in gene expression are likely to occur prior to the histological changes that distinguish malignant cells from normal cells. Using biomarkers that identify such changes in gene expression, one can identify cancerous or pre-cancerous cells when changes in gene expression are apparent, and thereby effectively target individuals who would most likely benefit from adjuvant therapy. However, the development of methods and compositions that permit early, rapid, and accurate detection of many forms of cancers continues to challenge the medical community. Thus, a significant problem in the treatment of cancer remains detection and prognosis to enable appropriate therapeutic treatment and ablation of cancer.
For example, prostate cancer (CaP) is one of the most common malignancies in men, with an increasing incidence. In 2007, approximately 218,900 men were diagnosed and approximately 27,050 men died of the disease in the U.S. alone. Despite important progress in the early diagnosis of prostate malignancies through the measurement of PSA levels, about 10% of newly diagnosed patients have some evidence of locally advanced CaP and 5% already have distant metastasis at the time of diagnoses (Draisma et al., (2003) J. Natl. Cancer Inst. 95:868-878; Thompson et al., (2003) N. Engl. J. Med. 349, 215-224; Makinen et al., (2003) Clin. Cancer Res. 9, 2435-2439). Curative treatments for locally advanced CaP are available (Bolla et al., (2002) Lancet 360, 103-106; Messing et al., (1999) N. Engl. J. Med. 341, 1781-1788; D'Amico et al., (2004) J. Am. Med. Assoc. 292, 821-827). In contrast, patients with evidence of distant metastases have a very poor prognosis and limited curative treatment exists (Cheville et al., (2002) Cancer 95, 1028-1036). Tumor metastasis is the main cause for mortality associated with prostate cancer. Hormone-refractory prostate cancer (HRPC) is an example of an invasive type of prostate cancer.
Limited treatment modalities currently exist for prostate cancer once it has metastasized. For example, systemic therapy is limited to various forms of androgen deprivation. While most patients will demonstrate initial clinical improvement, virtually inevitably, androgen-independent cells develop. Endocrine therapy is thus palliative, not curative. In a study of 1,387 patients with metastatic disease detectable by imaging (e.g., bone or CT scan), the median time to objective disease progression (excluding biochemical/PSA progression) after initiation of hormonal therapy (i.e., development of androgen-independence) was 16-48 months (Eisenberger M. A., et al. (1998) NEJM 339:1036-42). Median overall survival in these patients was 28-52 months from the onset of hormonal treatment (Eisenberger M. A., et al. (1998) supra.). Subsequent to developing androgen-independence, there is no effective standard therapy and the median duration of survival is 9-12 months (Vollmer, R. T., et al. (1999) Clin Can Res 5: 831-7; Hudes G., et al., (1997) Proc Am Soc Clin Oncol 16:316a (abstract); Pienta K. J., et al., (1994) J Clin Oncol 12(10):2005-12; Pienta K. J., et al. (1997) Urology 50:401-7; Tannock I. F., et al., (1996) J Clin Oncol 14:1756-65; Kantoff P. W., et al., (1996) J. Clin. Oncol. 15 (Suppl):25:110-25). Cytotoxic chemotherapy is poorly tolerated in this age group and generally considered ineffective and/or impractical. In addition, prostate cancer is relatively resistant to cytotoxic agents. Thus, chemotherapeutic regimen has not demonstrated a significant survival benefit in this patient group. In view of the shortcomings of existing therapies and diagnostics, the need still exists for improved targeted modalities for preventing, treating and/or diagnosing cancers, such as prostate cancer.